Quinazolinone and pyridopyrimidine a-II antagonists

ABSTRACT

Substituted quinazolinones and pyridopyrimidines of structural formula 1    &lt;IMAGE&gt;  1  are angiotensin II antagonists useful in the treatment of disorders related to the reninangiotensin system (RAS) such as hypertension, congestive heart failure, ocular hypertension and certain CNS disorders.

SUMMARY OF THE INVENTION

This invention is concerned with novel quinazolinones andpyridopyrimidines of structural formula I ##STR2## wherein X, Y and Zare carbons or a hetero-atoms such as nitrogen, oxygen or sulfur and Gis R¹ or ##STR3## R is usually alkyl and R¹ is an acidic function. Thecompounds are angiotensin II antagonists useful in the treatment ofdisorders related to the reninangiotensin system such as hypertension,and congestive heart failure.

This invention also relates to the use of the novel compounds andophthalmic formulations thereof in the topical treatment of ocularhypertension and glaucoma associated therewith.

This invention is also concerned with the use of the novel compounds inthe treatment of certain CNS disorders such as cognitive dysfunction.

The invention is also concerned with novel pharmaceutical and ophthalmicformulations comprising one of the novel compounds as active ingredienteither alone or in combination with other active ingredients.

Finally, the invention is concerned with novel processes for thepreparation of the novel compounds.

BACKGROUND OF THE INVENTION

The renin-angiotensin system (RAS) plays a central role in theregulation of normal blood pressure and seems to be critically involvedin hypertension development and maintenance as well as congestive heartfailure. Angiotension II (AII), an octapeptide hormone is producedmainly in the blood during the cleavage of angiotension I byangiotension converting enzyme (ACE) localized on the endothelium ofblood vessels of lung, kidney, and many other organs, and is the endproduct of the RAS. AII is a powerful arterial vasoconstricter thatexerts its action by interacting with specific receptors present on cellmembranes. One of the possible modes of controlling the RAS isangiotension II receptor antagonism. Several peptide analogs of AII areknown to inhibit the effect of this hormone by competitively blockingthe receptors, but their experimental and clinical applications havebeen limited by their partial agonist activity and lack of oralabsorption (M. Antonaccio. Clin. Exp. Hypertens. A4, 27-46 (1982); D. H.P. Streeten and G. H. Anderson, Jr. -Handbook of Hypertension, ClinicalPharmacology of Antihypertensive Drugs, ed. A. E. Doyle, Vol. 5, pp.246-271, Elsevier Science Publisher, Amsterdam, The Netherlands, 1984).

Recently, several non-peptide compounds have been described as AIIantagonists. Illustrative of such compounds are those disclosed in U.S.Pat. Nos. 4,207,324; 4,340,598; 4,576,958; 4,582,847 and 4,880,804 inEuropean Patent Applications 028,834; 245,637; 253,310; and 291,969; andin articles by A. T. Chiu, et al. (Eur. J. Pharm. Exp. Therap, 157,13-21 (1988)) and by P. C. Wong, et al. (J. Pharm. Exp. Therap, 247,1-7(1988), Hypertension, 13, 489-497 (1989)). All of the U.S. patents,European Patent Applications 028,834, 253,310, 399,731 and 400,974 andthe two articles disclose substituted imidazole compounds which aregenerally bonded through a lower alkyl bridge to a substituted phenyl.

Also, U.S. patent applications, Ser. Nos. 07/537,891 (filed Jun. 18,1990) and 07/665,389 (filed Mar. 6, 1991) disclose quinazolinones withsubstitution patterns different from those disclosed herein which arealso Angiotensin II antagonists.

DETAILED DESCRIPTION

The novel compounds of the invention are represented by structuralformula 1 ##STR4## or a pharmaceutically acceptable salt thereof,wherein. G is

(1) R¹ or ##STR5## E is (1) a single bond,

(2) --CH(OH)--,

(3) --O--,

(4) --CO--,

(5) --S(O)_(x) (CH₂)_(s) -- wherein x is 0, 1, or 2, and s is 0-5, or

(6) --NR³ (CH₂)_(s) -- wherein R³ is

(a) --H,

(b) C₂₋₄ alkanoyl,

(c) C₁₋₆ alkyl,

(d) C₂₋₆ alkenyl,

(e) C₃₋₇ cycloalkyl,

(f) phenyl, or

(g) benzyl;

R is

(1) aryl,

(2) heteroaryl,

(3) C₃₋₇ cycloalkyl,

(4) polyfluoro-C₁₋₄ alkyl,

(5) --H,

(6) C₂₋₆ alkenyl,

(7) C₂₋₆ alkynyl,

(8) C₁₋₆ alkyl, either unsubstituted or substituted with:

(a) aryl,

(b) C₃₋₇ cycloalkyl,

(c) halo,

(d) --NH₂,

(e) --NH(C₁₋₄ alkyl),

(f) --N(C₁₋₄ alkyl)₂,

(g) --OR⁴, wherein R⁴ is

(i) --H,

(ii) aryl,

(iii) heteroaryl,

(iv) C₁₋₆ alkyl, or

(v) aryl-C₁₋₆ alkyl;

(h) --COOR⁴,

(i) --NHSO₂ R⁴, or

(j) --SO₂ NHR⁵, wherein R⁵ is

(i) --H

(ii) C₁₋₅ alkyl,

(iii) aryl or,

(iv) --CH₂ -aryl;

R¹ is

(1) --CO₂ R⁴

(2) --SO₃ R⁶, wherein R⁶ is

(a)--H

(b)--CH(R⁴)--O--CO--R^(4a) wherein R^(4a) is

(i) C₁₋₆ alkyl,

(ii) aryl or

(iii) --CH₂ -aryl;

(3) --P(O)(OR⁶)₂,

(4) --CONHNHSO₂ CF₃,

(5) --SO₂ NHCN,

(6) --P(O)(OR⁶)(OR⁴),

(7) --SO₂ NHR⁷, wherein R⁷ is

(a) --H

(b) aryl,

(c) heteroaryl,

(d) C₃₋₇ cycloalkyl,

(e) polyfluoro-C₁₋₄ alkyl, or

(f) C₁₋₁₀ alkyl, either unsubstituted or substituted with:

(i) aryl,

(ii) heteroaryl,

(iii) --OH,

(iv) --SH,

(v) C₁₋₄ alkoxy,

(vi) C₁₋₄ alkylthio

(vii) halo

(viii) --NO₂

(ix) --CO₂ R¹¹, wherein R¹¹ is --H or C₁₋₄ alkyl,

(x) --NH₂,

(xi) --NH(C₁₋₄ alkyl)

(xii) --N(C₁₋₄ alkyl)₂

(xiii) --PO₃ H₂,

(xiv) --P(O)(OH) (OC₁₋₄ alkyl), or

(xv) --P(O)(OR⁴)(R⁸) wherein R⁸ is

(a) --H

(b) C₁₋₅ alkyl,

(c) aryl or

(d) --CH₂ -aryl,

(8) --NHSO₂ R⁷,

(9) --SO₂ NHCOR⁷,

(10) --CH₂ SO₂ NHCOR⁷,

(11) --CONHSO₂ R⁷,

(12) --CH₂ CONHSO₂ R⁷,

(13) --NHSO₂ NHCOR⁷,

(14) --NHCONHSO₂ R⁷,

(15) --SO₂ NHCONR⁴ R⁷,

(16) --CH₂ SO₂ NHR⁷,

(17) --C(OH)(R⁸)--P(O) (OR⁶)₂,

(18) --P(O)(R⁸)(OR⁶),

(19) tetrazol-5-yl, substituted with R⁹ wherein R⁹ is

(a) --H,

(b) C₁₋₆ alkyl,

(c) C₂₋₄ alkenyl,

(d) C₁₋₄ alkoxy-C₁₋₄ alkyl

(e) benzyl, either unsubstituted or substituted with

(i) --NO₂,

(ii) --NH₂,

(iii) --OH, or

(iv) --OCH₃,

(20) --CH₂ -tetrazol-5-yl substituted with R⁹,

(21) --CONH-tetrazol-5-yl substituted with R⁹,

(22) -1,3,4-triazol-2-yl substituted with R¹⁰ wherein R¹⁰ is

(a) --CN,

(b) --NO₂,

(c) --CF₃ or

(d) --CO₂ R⁴ ;

(23) 1,2,3-triazol-4-yl substituted with R¹⁰,

(24) --SO₂ NHSO₂ R⁷,

(25) --OH or ##STR6## R² is: (1) --H,

(2) --CO-aryl,

(3) C₃₋₇ cycloalkyl,

(4) halo,

(5) --OH,

(6) --OR⁷,

(7) polyfluoro-C₁₋₄ alkyl,

(8) --S(O)_(x) R⁷,

(9) --COOR⁴,

(10) --SO₂ H,

(11) --NR⁴ R⁷,

(12) --NHCOR⁷,

(13) --NHCO₂ R⁷

(14) --SO₂ NR⁸ R¹¹, wherein R¹¹ is

(a) --H or

(b) C₁₋₄ alkyl,

(15) --NO₂,

(16) --NHSO₂ R⁷,

(17) --NHCONR⁴ R⁷,

(18) --OCONR⁷ R⁸,

(19) aryl,

(20) heteroaryl,

(21) --NHSO₂ --polyfluorophenyl,

(22) --SO₂ NH--heteroaryl,

(23) --SO₂ NHCOR⁷,

(24) --CONHSO₂ R⁷,

(25) --PO(OR⁴)₂,

(26) --PO(OR⁴)R⁸,

(27) tetrazol-5-yl,

(28) --CONH(tetrazol-5-yl),

(29) --COR₄

(30) --SO₂ NHCN,

(31) --CO-heteroaryl,

(32) --NHSO₂ NR⁷ R⁸, or

(33) C₁₋₆ alkyl, either unsubstituted or substituted with

(a) --OH,

(b) --guanidino,

(c) --C₁₋₄ alkoxy,

(d) --N(R⁴)₂,

(e) --CO₂ R⁴,

(f) --CON(R⁴)₂,

(g) --O--COR⁴

(h) -aryl,

(i) -heteroaryl,

(j) --S(O)_(x) R⁷

(k) -tetrazol-5-yl,

(l) --CONHSO₂ R⁷,

(m) --SO₂ NH--heteroaryl,

(n) --SO₂ NHCOR⁷,

(o) --PO(OR⁴)₂,

(p) --PO(OR⁴)R⁹,

(q) --SO₂,NHCN,

(r) --NR¹¹ COOR⁷,

(s) --morpholino,

(t) --N(C₁₋₆ alkyl) piperazine or

(u) --COR⁴, with the proviso that the R² substituents can be the same ordifferent; or if attached to the same carbon, two R² groups takentogether represent:

(a)=O,

(b)=S or

(c) --[(CH₂)₂₋₆ ]--;

R^(2a), R^(2b), R^(3a) and R^(3b) independently represent:

(1) C₁₋₅ alkyl,

(2) polyfluoro-C₁₋₅ alkyl,

(3) halo,

(4) hydroxy or

(5) C₁₋₅ alkoxy;

U, V and W are independently --CH═ or --N═ provided no more than one ofU, V and W is --N═ at one time;

Z is:

(1) --O--,

(2) --S(O)_(x) --,

(3) --N(R¹²)--wherein R¹² is

(a) --H or

(b) --R¹³ wherein R¹³ is

(i) C₁₋₄ alkyl,

(ii) C₃₋₇ cycloalkyl

(iii) aryl,

(iv) heteroaryl,

(v) polyfluoro-C₁₋₄ alkyl,

(vi) polyfluoro-C₃₋₇ cycloalkyl or

(vii) polyfluorophenyl;

(4) --N(COR¹³)--,

(5) --N(CONHR¹³)--,

(6) --N(CON(R¹³)₂)--,

(7) --N(CO₂ R¹³)--,

(8) --N(SO₂ NHR¹³)--,

(9) --N(SO₂ N(R¹³)₂)--,

(10) --N(SO₂ R¹³)--, or

(11) --C(R²)₂ --,

X is:

(1) a single bond

(2) --SO₂ --

(3) --O--

(4) --C(R²)₂ --

(5) --N(R¹²)--

(6) --N(COR¹³)--

(7) --N(CONHR¹³)--

(8) --N(CON(R¹³)₂)--

(9) --N(CO₂ R¹³)--

(10) --N(SO₂ NHR¹³)--

(11) --N(SO₂ N(R¹³)₂)--

(12) --N(SO₂ R¹³)--

Y is:

(1) --O--

(2) --S(O)_(x) -- where x is 0, 1, or 2,

(3) --C(R²)₂ --

(4) --N(R¹²)--

(5) --N(COR¹³)--

(6) --N(CONHR¹³)--

(7) --N(CON(R¹³)₂)--

(8) --N(CO₂ R¹³)--

(9) --N(SO₂ NHR¹³)--

(10) --N(SO₂ N(R¹³)₂)--

(11) --N(SO₂ R¹³)--

The terms "alkyl", "alkenyl", "alkynyl" and the like include both thestraight chain and branched chain species of these generic terms whereinthe number of carbon atoms in the species permit. Unless otherwisenoted, the specific names for these generic terms shall mean thestraight chain species. For example, the term "butyl" shall mean thenormal butyl substituent, n-butyl.

The term "aryl" means phenyl or naphthyl either unsubstituted orsubstituted with one or two substituents which may be the same ordifferent and are selected from the group consisting of halo, --NR⁴,--CO₂ R⁴, C₁₋₄ alkyl, C₁₋₄ alkoxy, --NO₂, --CF₃, --OH and C₁₋₄alkylthio.

The term "heteroaryl" means a 5- or 6-membered aromatic ring comprising1 to 3 heteratoms selected from O, N and S such as triazole, imidazole,thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, pyridine,pyrazine, pyrimidine, or the like, either unsubstituted or substitutedwith 1 or 2 substituents selected from --OH, --SH, C₁₋₄ alkyl, C₁₋₄alkoxy, --CF₃, halo, --NO₂, --CO₂ R¹¹, or --N(R¹¹)₂ wherein the R¹¹substituents are the same or different.

The term "halo" or "halogen", means --Cl, --Br, --I or --F.

One embodiment of the novel compounds of this invention is that whereinG is ##STR7##

A class of compounds within this embodiment is that wherein:

E is

(1) a single bond,

(2) --O-- or

(3) --S--;

R is

(1) C₁₋₆ alkyl, either unsubstituted or substituted with

(a) C₃₋₅ cycloalkyl,

(b) --Cl,

(c) --CF₃,

(d) --OCH₃,

(e) --OC₂ H₅,

(f) --SCH₃,

(g) --SC₂ H₅,

(h) --F, or

(i) phenyl;

(2) C₂₋₅ alkenyl,

(3) C₂₋₅ alkynyl, or

(4) C₃₋₅ cycloalkyl;

R¹ is

(1) --CO₂ H,

(2) tetrazol-5-yl,

(3) --NHSO₂ R⁷,

(4) --SO₂ NH-heteroaryl,

(5) --CH₂ SO₂ NH-heteroaryl,

(6) --SO₂ NHCOR⁷,

(7) --CH₂ SO₂ NHCOR⁷,

(8) --CONHSO₂ R⁷,

(9) --CH₂ CONHSO₂ R⁷,

(10) --NHSO₂ NHCOR⁷,

(11) --NHCONHSO₂ R⁷,

(12) --SO₂ NHCON(R⁴)R⁷, or ##STR8## (14) --SO₂ NHSO₂ R⁷ R² is:

(1)--H

(2) C₁₋₄ alkyl, either unsubstituted or substituted with:

(a) --CO₂ R⁴,

(b) --OCOR^(4a),

(c) --OH, or

(d) aryl;

(3) C₂₋₄ alkenyl,

(4) --OH,

(5) --NO₂,

(6) --NHCOR⁷,

(7) C₁₋₄ alkoxy,

(8) --NHCO₂ R⁷,

(9) --NR⁴ R⁷ or

(10) --Cl, --F, or --Br; or two R² groups on the same carbon takentogether represent =O or --(CH₂)₂₋₅ --; and

X is

(1) --C(R²)₂ -- or

(2) a single bond;

Y is

(1) --C(R²)₂ -- or

(2) --N(R¹²)--;

Z is

(1) --N(R¹²)--,

(2) --C(R²)₂ -- or

(3) --O--;

(4) --S(O)_(x) -- where x=0, 1, or 2.

Illustrative of this class of compounds are those shown in Table I andthe Examples which follow:

                  TABLE I                                                         ______________________________________                                         ##STR9##                                                                      ##STR10##                                                                            W        Y           Z         R.sup.1                                ______________________________________                                        1.      CH       CH.sub.2                                                                                  ##STR11## 1                                      2.      CH       CH.sub.2                                                                                  ##STR12## 2                                      3.      CH       CH.sub.2                                                                                  ##STR13## 4                                      4.      CH       CH.sub.2                                                                                  ##STR14## 7                                      5.      CH       CH.sub.2                                                                                  ##STR15## 1                                      6.      CH       CH.sub.2                                                                                  ##STR16## 2                                      7.      CH       CH.sub.2                                                                                  ##STR17## 4                                      8.      CH       CH.sub.2                                                                                  ##STR18## 6                                      9.      CH       CH.sub.2                                                                                  ##STR19## 7                                      10.     CH        CO                                                                                       ##STR20## 1                                      11.     CH       CO                                                                                        ##STR21## 2                                      12.     CH       CO                                                                                        ##STR22## 4                                      13.     CH       CO                                                                                        ##STR23## 6                                      14.     CH       CO                                                                                        ##STR24## 7                                      15.     CH       CO                                                                                        ##STR25## 1                                      16.     CH       CO                                                                                        ##STR26## 2                                      17.     CH       CO                                                                                        ##STR27## 4                                      18.     CH       CO                                                                                        ##STR28## 6                                      19.     CH       CO                                                                                        ##STR29## 7                                      20.     CH       CH.sub.2   O          1                                      21.     CH       CH.sub.2   O          2                                      22.     CH       CH.sub.2   O          4                                      23.     CH       CH.sub.2   O          6                                      24.     CH       CH.sub.2   SO.sub.2   1                                      25.     CH       CH.sub.2   SO.sub.2   2                                      26.     CH       CH.sub.2   SO.sub.2   4                                      27.     CH       CH.sub.2   SO.sub.2   6                                      28.     CH       CH.sub.2   SO.sub.2   7                                      29.     CH       CH.sub.2                                                                                  ##STR30## 1                                      30.     CH       CH.sub.2                                                                                  ##STR31## 2                                      31.     CH       CH.sub.2                                                                                  ##STR32## 4                                      32.     CH       CH.sub.2                                                                                  ##STR33## 6                                      33.     CH       CH.sub.2                                                                                  ##STR34## 7                                      34.     CH       CH.sub.2                                                                                  ##STR35## 1                                      35.     CH       CH.sub.2                                                                                  ##STR36## 2                                      36.     CH       CH.sub.2                                                                                  ##STR37## 4                                      37.     CH       CH.sub.2                                                                                  ##STR38## 6                                      38.     CH       CH.sub.2                                                                                  ##STR39## 7                                      39.     N        CH.sub.2                                                                                  ##STR40## 1                                      40.     N        CH.sub.2                                                                                  ##STR41## 2                                      41.     N        CH.sub.2                                                                                  ##STR42## 4                                      42.     N         CH.sub.2                                                                                 ##STR43## 7                                      43.     N        CH.sub.2                                                                                  ##STR44## 1                                      44.     N        CH.sub.2                                                                                  ##STR45## 2                                      45.     N        CH.sub.2                                                                                  ##STR46## 4                                      46.     N        CH.sub.2                                                                                  ##STR47## 6                                      47.     N        CH.sub.2                                                                                  ##STR48## 7                                      48.     N        CO                                                                                        ##STR49## 1                                      49.     N        CO                                                                                        ##STR50## 2                                      50.     N        CO                                                                                        ##STR51## 4                                      51.     N        CO                                                                                        ##STR52## 6                                      52.     N         CO                                                                                       ##STR53## 7                                      53.     N        CO                                                                                        ##STR54## 1                                      54.     N        CO                                                                                        ##STR55## 2                                      55.     N        CO                                                                                        ##STR56## 4                                      56.     N        CO                                                                                        ##STR57## 6                                      57.     N        CO                                                                                        ##STR58## 7                                      58.     N        CH.sub.2   O          1                                      59.     N        CH.sub.2   O          2                                      60.     N        CH.sub.2   O          4                                      61.     N        CH.sub.2   O          6                                      62.     N        CH.sub.2   SO.sub.2   1                                      63.     N        CH.sub.2   SO.sub.2   2                                      64.     N        CH.sub.2   SO.sub.2   4                                      65.     N        CH.sub.2   SO.sub.2   6                                      66.     N        CH.sub.2   SO.sub.2   7                                      67.     N        CH.sub.2                                                                                  ##STR59## 1                                      68.     N        CH.sub.2                                                                                  ##STR60## 2                                      69.     N        CH.sub.2                                                                                  ##STR61## 4                                      70.     N        CH.sub.2                                                                                  ##STR62## 6                                      71.     N        CH.sub.2                                                                                  ##STR63## 7                                      72.     N        CH.sub.2                                                                                  ##STR64## 1                                      73.     N        CH.sub.2                                                                                  ##STR65## 2                                      74.     N        CH.sub.2                                                                                  ##STR66## 4                                      75.     N        CH.sub.2                                                                                  ##STR67## 6                                      76.     N        CH.sub.2                                                                                  ##STR68## 7                                      ______________________________________                                    

Another embodiment of the novel compounds of this invention is thatwherein G is R¹.

A class of compounds within this embodiment is that wherein:

E is

(1) a single bond,

(2) --O-- or

(3) --S--;

R is

(1) C₁₋₆ alkyl, either unsubstituted or substituted with

(a) C₃₋₅ cycloalkyl,

(b) --Cl,

(c) --CF₃,

(d) --OCH₃,

(e) --OC₂ H₅,

(f) --SCH₃,

(g) --SC₂ H₅,

(h) --F, or

(i) phenyl;

(2) C₂₋₅ alkenyl,

(3) C₂₋₅ alkynyl, or

(4) C₃₋₅ cycloalkyl;

R¹ is

(1) --CO₂ H,

(2) tetrazol-5-yl,

(3) --NHSO₂ R⁷,

(4) --SO₂ NH-heteroaryl,

(5) --CH₂ SO₂ NH-heteroaryl,

(6) --SO₂ NHCOR⁷,

(7) --CH₂ SO₂ NHCOR⁷,

(8) --CONHSO₂ R⁷,

(9) --CH₂ CONHSO₂ R⁷,

(10) --NHSO₂ NHCOR⁷,

(11) --NHCONHSO₂ R⁷,

(12) --SO₂ NHCON(R⁴)R⁷ or ##STR69## R² is: (1)--H,

(2) C₁₋₄ alkyl, either unsubstituted or substituted with:

(a) --CO₂ R⁴,

(b) --OCOR^(4a),

(c) --OH, or

(d) aryl;

(3) C₂₋₄ alkenyl,

(4) --OH,

(5) --NO₂,

(6) --NHCOR⁷,

(7) C₁₋₄ alkoxy,

(8) --NHCO₂ R⁷,

(9) --NR⁴ R⁷ or

(10) --Cl, --F, or --Br; or two R² groups on the same carbon takentogether represent=O or --(CH₂)₂₋₅ --;

Z is

(1) --N(R¹²)--,

(2) --C(R²)₂ --, or

(3) --O--,

X is

(1) --C(R²)₂ -- or

(2) a single bond; and

Y is

(1) --C(R²)₂ -- or

(2) --N (R¹²)--.

Illustrative of this class of compounds are those shown in Table II andthe Examples which follow:

                                      TABLE II                                    __________________________________________________________________________     ##STR70##                                                                     RE          R.sup.1                                                                                      ##STR71##                                         __________________________________________________________________________    n-C.sub.3 H.sub.7O                                                                        CO.sub.2 H                                                                                    ##STR72##                                          ##STR73##                                                                                 ##STR74##                                                                                    ##STR75##                                         CH.sub.2CHCH.sub.2                                                                        NHSO.sub.2 CH.sub.3                                                                           ##STR76##                                          ##STR77##                                                                                 ##STR78##                                                                                    ##STR79##                                         CF.sub.3 CH.sub.2 CH.sub.2                                                                CONHSO.sub.2 C.sub.2 H.sub.5                                                                  ##STR80##                                         n-C.sub.3 H.sub.7S                                                                        SO.sub.2 NHCON(C.sub.2 H.sub.5).sub.2                                                         ##STR81##                                          ##STR82##                                                                                 ##STR83##                                                                                    ##STR84##                                         n-C.sub.4 H.sub.9                                                                         CH.sub.2 CONHSO.sub.2 CH.sub.3                                                                ##STR85##                                         F(CH.sub.2).sub.3                                                                          ##STR86##                                                                                    ##STR87##                                         n-C.sub.3 H.sub.7                                                                         NHCONHSO.sub.2 CH.sub.3                                                                       ##STR88##                                         n-C.sub.3 H.sub.7                                                                         NHCONHSO.sub.2 CH.sub.3                                                                       ##STR89##                                         n-C.sub.3 H.sub.7                                                                         NHCONHSO.sub.2 CH.sub.3                                                                       ##STR90##                                         n-C.sub.3 H.sub.7                                                                         NHCONHSO.sub.2 CH.sub.3                                                                       ##STR91##                                         __________________________________________________________________________

The compounds of this invention are prepared in accordance with thefollowing Reaction Schemes: ##STR92##

The steps used in Scheme I from the nitrobenzonitrile 4 to the finalproduct 8 are the same as for 13 to final product. ##STR93##

The steps used in Scheme 1 from the nitrobenzonitrile 4 to the finalproduct 8 are the same as for 15 to final product. ##STR94##

The steps used in Scheme 1 from the nitrobenzonitrile 4 to the finalproduct 8 are the same as for 18 to final product. ##STR95##

Quinazolinone 24 may carried on to the final product using the samemethods used for 6 in Scheme 1. ##STR96##

Commercially available 25 may be converted to the nitrile derivative 26(see N. L. Colbry, E. F. Elslager, L. M. Werbel, J. Heterocyclic Chem.,(1984), 21, 1521-1525) then to the aminated derivative 27 as shown inScheme 6. The pyridine 27 may then be converted to the correspondingpyridopyrimidine following the procedures as used for intermediate 4 asshown in Scheme 1.

    ______________________________________                                        Abbreviations                                                                 ______________________________________                                        DMF            Dimethyl formamide                                             Me             Methyl                                                         Et             Ethyl                                                          t-BOC          t-Butoxycarbonyl                                               DMSO           Dimethyl sulfoxide                                             DMAP           4-dimethylaminopyridine                                        EtOAc          Ethyl acetate                                                  Et.sub.2 O     Diethyl ether                                                  AcOH           Acetic acid                                                    TFA            Trifluoracetic acid                                            NMP            N-methyl-2-pyrrolidinone                                       ______________________________________                                    

The novel process of this invention comprises the condensation ofcompounds VI and VII to yield VIII. To one skilled in the art it will beapparent that if Z in a final product is --NH-- or a nitogen with afunctional group substituent, that nitrogen will require protectionduring this step followed by deprotection if desired. Similarly if R¹##STR97## has a terminal nitrogen such as in --SO² NH₂, it also willrequire appropriate protection followed by deprotection andderivatization if desired.

The condensation is conducted in a polar aprotic solvent such as DMF, orDMSO, in the presence of a strong base such as: an alkali metal hydridepreferably sodium hydride; an alkali metal alkane or aromatic such asn-butyl lithium, or phenyl lithium or the like. The reaction temperatureis not critical and may be conducted at about 0° C. to about 100° C.,but preferably and most conveniently at about room temperature or about20°-30° C. The time required for the reaction to go to completion willdepend on the temperature, and will vary from about 4 hours to about 24hours. It is convenient to let it proceed for about 16 hours (overnight)at about room temperature.

t-Butyl or t-BOC protective groups are readily removed by treating theprotected compound with anisole in TFA overnight at about roomtemperature.

The deprotected nitrogens can readily be acylated by treatment with theappropriate acyl chloride in the presence of a catalyst such as DMAP andan acid acceptor such as Et₃ N or pyridine in a solvent such aspyridine, CH₂ Cl₂ or the like.

The compounds of this invention form salts with various inorganic andorganic acids and bases which are also within the scope of theinvention. Such salts include ammonium salts, alkali metal salts likesodium and potassium salts, alkaline earth metal salts like the calciumand magnesium salts, salts with organic bases; e.g., dicyclohexylaminesalts, N-methyl-D-glucamine salts, salts with amino acids like arginine,lysine, and the like. Also, salts with organic and inorganic acids maybe prepared; e.g., HCl, HBr, H₂ SO₄, H₃ PO₄, methanesulfonic,toluenesulfonic, maleic, fumaric, camphorsulfonic. The non-toxic,physiologically acceptable salts are preferred, although other salts arealso useful, e.g., in isolating or purifying the product.

The salts can be formed by conventional means such as by reacting thefree acid or free base forms of the product with one or more equivalentsof the appropriate base or acid in a solvent or medium in which the saltis insoluble, or in a solvent such as water which is then removed invacuo or by freezedrying or by exchanging the cations of an existingsalt for another cation on a suitable ion exchange resin.

Angiotensin II (AII) is a powerful arterial vasoconstrictor, and itexerts its action by interacting with specific receptors present on cellmembranes. The compounds described in the present invention act ascompetitive antagonists of AII at the receptors. In order to identifyAII antagonists and determine their efficacy in vitro, the following twoligand-receptor binding assays were established.

Receptor Binding Assay Using Rabbit Aortae Membrane Preparation

Three frozen rabbit aortae (obtained from Pel-Freeze Biologicals) weresuspended in 5 mM Tris-0.25M Sucrose, pH 7.4 buffer (50 ml),homogenized, and then centrifuged. The mixture was filtered through acheesecloth and the supernatant was centrifuged for 30 minutes at 20,000rpm at 4° C. The pellet thus obtained was resuspended in 30 ml of 50 mMTris-5 mM MgCl₂ buffer containing 0.2% Bovine Serum Albumin and 0.2mg/ml Bacitracin, and the suspension was used for 100 assay tubes.Samples tested for screening were done in duplicate. To the membranepreparation (0.25 ml) there was added ¹²⁵ I-Sar¹ Ile⁸ -angiotensin II[obtained from New England Nuclear] (10 μl; 20,000 cpm) with or withoutthe test sample, and the mixture was incubated at 37° C. for 90 minutes.The mixture was then diluted with ice-cold 50 mM Tris-0.9% NaCl, pH 7.4(4 ml) and filtered through a glass fiber filter (GF/B Whatman 2.4"diameter). The filter was soaked in scintillation cocktail (10 ml) andcounted for radioactivity using Packard 2660 Tricarb liquidscintillation counter. The inhibitory concentration (IC₅₀) of potentialAII antagonist, which gives 50% displacement of the total specificallybound ¹²⁵ I-Sar¹ Ile⁸ -angiotensin II, was presented as a measure of theefficacy of such compounds as AII antagonists.

Receptor Assay Using Bovine Adrenal Cortex Preparation

Bovine adrenal cortex was selected as the source of AII receptor.Weighed tissue (0.1 g is needed for 100 assay tubes) was suspended inTris.HCl (50 mM), pH 7.7 buffer and homogenized. The homogenate wascentrifuged at 20,000 rpm for 15 minutes. Supernatant was discarded andpellets resuspended in buffer [Na₂ HPO₄ (10 mM)-NaCl (120 mM)-disodiumEDTA (5 mM) containing phenylmethanesulfonyl fluoride (PMSF)(0.1 mM)].(For screening of compounds generally duplicates of tubes are used). Tothe membrane preparation (0.5 ml) there was added ³ H-angiotensin II (50mM) (10 μl), with or without the test sample, and the mixture wasincubated at 37° C. for 1 hour. The mixture was then diluted with Trisbuffer (4 ml) and filtered through a glass fiber filter (GF/B Whatman2.4" diameter). The filter was soaked in scintillation cocktail (10 ml)and counted for radioactivity using Packard 2660 Tricarb liquidscintillation counter. The inhibitory concentration (IC₅₀) of potentialAII antagonist, which gives 50% displacement of the total specificallybound ³ H-angiotensin II, was presented as a measure of the efficacy ofsuch compounds as AII antagonists.

Using the methodology described above, representative compounds of theinvention were evaluated and were found to exhibit an activity ofatleast IC₅₀ <50 μM, thereby demonstrating and confirming the utility ofthe compounds of the invention as effective AII antagonists.

The potential antihypertensive effects of the compounds described in thepresent invention may be evaluated using the methodology describedbelow:

Male Charles River Sprague-Dawley rats (300-375 gm) were anesthetizedwith methohexital (Brevital; 50 mg/kg i.p.). The trachea was cannulatedwith PE 205 tubing. A stainless steel pithing rod (1.5 mm thick, 150 mmlong) was inserted into the orbit of the right eye and down the spinalcolumn. The rats were immediately placed on a Harvard Rodent Ventilator(rate--60 strokes per minute, volume--1.1 cc per 100 grams body weight).The right carotid artery was ligated, both left and right vagal nerveswere cut, the left carotid artery was cannulated with PE 50 tubing fordrug administration, and body temperature was maintained at 37° C. by athermostatically controlled heating pad which received input from arectal temperature probe. Atropine (1 mg/kg i.v.) was then administeredand 15 minutes later propranolol (1 mg/kg i.v.). Thirty minutes laterantagonists of formula I were administered intravenously or orally.Angiotensin II was then typically given at 5, 10, 15, 30, 45 and 60minute intervals and every half-hour thereafter for as long as the testcompound showed activity. The change in the mean arterial blood pressurewas recorded for each angiotensin II challenge and the percentinhibition of the angiotensin II response was calculated.

Thus, the compounds of the invention are useful in treatinghypertension. They are also of value in the management of acute andchronic congestive heart failure and angina. These compounds may also beexpected to be useful in the treatment of primary and secondaryhyperaldosteronism; renal diseases such a diabetic nephropathy,glomerulonephritis, glomerular sclerosis, nephrotic syndrome,hypertensive nephrosclerosis, end stage, renal disease, used in renaltransplant therapy, and to treat renovascular hypertension, sclerderma,left ventricular dysfunction, systolic and diasystolic dysfunction,diabetic retinopathy and in the management of vascular disorders such asmigraine, Raynaud's disease, and as prophylaxis to minimize theatherosclerotic process and neointimal hyperplasia following angioplastyor vascular injury and to retard the onset of type II diabetes. Theapplication of the compounds of this invention for these and similardisorders will be apparent to those skilled in the art.

The compounds of this invention are also useful to treat elevatedintraocular pressure and to enhance retinal blood flow and can beadministered to patients in need of such treatment with typicalpharmaceutical formulations such as tablets, capsules, injectables andthe like as well as topical ocular formulations in the form ofsolutions, ointments, inserts, gels, and the like. Pharmaceuticalformulations prepared to treat intraocular pressure would typicallycontain about 0.1% to 15% by weight, preferably 0.5% to 2% by weight, ofa compound of this invention. For this use, the compounds of thisinvention may also be used in combination with other medications for thetreatment of glaucoma including choline esterase inhibitors such asphysostigmine salicylate or demecarium bromide, parasympathomineticagents such as pilocarpine nitrate, -adrenergic antagonists such astimolol maleate, adrenergic agonists such as epinephrine and carbonicanhydrase inhibitors such as MK-507.

In the management of hypertension and the clinical conditions notedabove, the compounds of this invention may be utilized in compositionssuch as tablets, capsules or elixirs for oral administration,suppositories for rectal administration, sterile solutions orsuspensions for parenteral or intramuscular administration, and thelike. The compounds of this invention can be administered to patients(animals and human) in need of such treatment in dosages that willprovide optimal pharmaceutical efficacy. Although the dose will varyfrom patient to patient, depending upon the nature and severity ofdisease, the patient's weight, special diets then being followed by apatient, concurrent medication and other factors, which those skilled inthe art will recognize, the dosage range will generally be about 1 to1000 mg. per patient per day which can be administered in single ormultiple doses. Perferably, the dosage range will be about 5 to 500 mg.per patient per day; more preferably about 5 to 300 mg. per patient perday.

The compounds of this invention can also be administered in combinationwith other antihypertensives and/or diuretics. For example, thecompounds of this invention can be givein in combination with diureticssuch as hydrochlorothiazide, chlorothiazide, chlorothalidone,methyclothiazide, furosemide, ethacrynic acid, triamterene, amiloride,atriopeptin and spironolactone; calcium channel blocker, such asdiltiazem, felodipine, nifedipine, amlodipine, nimodipine, isradipine,nitrendipine and verapamil; β-adrenergic antagonists such as timolol,atenolol, metoprolol, propanolol, nadolol and pindolol; angiotensinconverting enzyme inhibitors such as enalapril, lisinopril, captopril,ramipril, quinapril and zofenopril; renin inhibitors such as A-69729, FK906 and FK 744; α-adrenergic antagonists such as prazosin, doxazosin,and terazosin; sympatholytic agents such as methyldopa, (alone or withANP) clonidine and guanabenz, atriopeptidase inhibitors (alone or withANP) such as UK-79300; serotonin antagonists such as ketanserin; A₂-adenosine receptor agonists such as CGS 22492C; potassium channelagonists such as pinacidil and cromakalim; and various otherantihypertensive drugs including reserpine, minoxidil, guanethidine,hydralazine hydrochloride and sodium nitroprusside as well ascombination of the above-named drugs as well as admixtures andcombinations thereof.

Combinations useful in the management of congestive heart failureinclude, in addition, compounds of this invention with cardiacstimulants such as dobutamine and xamoterol and phosphodiesteraseinhibitors including amrinone and mirinone.

Typically, the individual daily dosages for these combinations can rangefrom about one-fifth of the minimally recommended clinical dosages tothe maximum recommended levels for the entities when they are givensingly.

To illustrate these combinations, one of the angiotensin II antagonistsof this invention effective clinically in the 5-500 milligrams per dayrange can be effectively combined at levels at the 1.0-500 milligramsper day range with the following compounds at the indicated per day doserange: hydrochlorothiazide (6-100 mg) chlorothiazide (125-500 mg),ethacrynic acid (5-200 mg), amiloride (5-20 mg), furosemide (5-80 mg),propranolol (10-480 mg), timolol maleate (1-20 mg.), methyldopa(125-2000 mg), felodipine (1-20 mg), nifedipine (5-120 mg), nitrendipine(5-60 mg) and diltizaem (30-540 mg). In addition, triple drugcombinations of hydrochlorothiazide (5-100 mg) plus amiloride (5-20 mg)plus angiotensin II antagonist of this invention (1-500 mg) orhydrochlorothiazide (5-100 mg) plus timolol maleate (5-60) plus anangiotensin II antagonist of this invention (1-500 mg) orhydrochlorothiazide (5-200 mg) and nifedipine (5-60 mg) plus anangiotensin II antagonist of this invention (1-500 mg) are effectivecombinations to control blood pressure in hypertensive patients.Naturally, these dose ranges can be adjusted on a unit basis asnecessary to permit divided daily dosage and, as noted above, the dosewill vary depending on the nature and severity of the disease, weight ofpatient, special diets and other factors.

Typically, these combinations can be formulated into pharmaceuticalcompositions as discussed below.

About 1 to 100 mg. of compound or mixture of compounds of Formula I or aphysiologically acceptable salt is compounded with a physiologicallyacceptable vehicle, carrier, excipient, binder, preservative,stabilizer, flavor, etc., in a unit dosage form as called for byaccepted pharmaceutical practice. The amount of active substance inthese compositions or preparations is such that a suitable dosage in therange indicated is obtained.

Illustrative of the adjuvants which can be incorporated in tablets,capsules and the like are the following: a binder such as gumtragacanth, acacia, corn starch or gelatin; an excipient such asmicrocrystalline cellulose; a disintegrating agent such as corn starch,pregelatinized starch, alginic acid and the like; a lubricant such asmagnesium stearate; a sweetening agent such as sucrose, lactose orsaccharin; a flavoring agent such as peppermint, oil of wintergreen orcherry. When the dosage unitform is a capsule, it may contain, inaddition to materials of the above type, a liquid carrier such as fattyoil. Various other materials may be present as coatings or to otherwisemodify the physical form of the dosage unit. For instance, tablets maybe coated with shellac, sugar or both. A syrup or elizir may contain theactive compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

Sterile compositions for injection can be formulated according toconventional pharmaceutical practice by dissolving or suspending theactive substance in a vehicle such as water for injection, a naturallyoccurring vegetable oil like sesame oil, coconut oil, peanut oil,cottonseed oil, etc., or a synthetic fatty vehicle like ethyl oleate orthe like. Buffers, preservatives, antioxidants and the like can beincorporated as required.

The useful central nervous system (CNS) activities of the compounds ofthis invention are demonstrated and exemplified by the ensuing assays.

COGNITIVE FUNCTION ASSAY

The efficacy of these compounds to enhance cognitive function can bedemonstrated in a rat passive avoidance assay in which cholinomimeticssuch as physostigmine and nootropic agents are known to be active. Inthis assay, rats are trained to inhibit their natural tendency to enterdark areas. The test apparatus used consists of two chambers, one ofwhich is brightly illuminated and the other is dark. Rats are placed inthe illuminated chamber and the elapsed time it takes for them to enterthe darkened chamber is recorded. On entering the dark chamber, theyreceive a brief electric shock to the feet. The test animals arepretreated with 0.2 mg/kg of the muscarinic antagonist scopolamine whichdisrupts learning or are treated with scopolamine and the compound whichis to be tested for possible reversal of the scopolamine effect.Twenty-four hours later, the rats are returned to the illuminatedchamber. Upon return to the illuminated chamber, normal young rats whohave been subjected to this training and who have been treated only withcontrol vehicle take longer to re-enter the dark chamber than testanimals who have been exposed to the apparatus but who have not receiveda shock. Rats treated with scopolamine before training do not show thishesitation when tested 24 hours later. Efficacious test compounds canovercome the disruptive effect on learning which scopolamine produces.Typically, compounds of this invention should be efficacious in thispassive avoidance assay in the dose range of from about 0.1 mg/kg toabout 100 mg/kg.

ANXIOLYTIC ASSAY

The anxiolytic activity of the invention compounds can be demonstratedin a conditioned emotional response (CER) assay. Diazepam is aclinically useful anxiolytic which is active in this assay. In the CERprotocol, male Sprague-Dawley rats (250-350 g) are trained to press alever on a variable interval (VI) 60 second schedule for foodreinforcement in a standard operant chamber over weekly (five days perweek) training sessions. All animals then receive daily 20 minuteconditioning sessions, each session partitioned into alternating 5minute light (L) and 2 minute dark (D) periods in a fixed L1D1L2D2L3sequence. During both periods (L or D), pressing a lever delivers foodpellets on a VI 60 second schedule: in the dark (D), lever presses alsoelicit mild footshock (0.8 mA, 0.5 sec) on an independent shockpresentation schedule of VI 20 seconds. Lever pressing is suppressedduring the dark periods reflecting the formation of a conditionedemotional response (CER).

Drug testing in this paradigm is carried out under extinctionconditions. During extinction, animals learn that responding for food inthe dark is no longer punished by shock. Therefore, response ratesgradually increase in the dark periods and animals treated with ananxiolytic drug show a more rapid increase in response rate than vehicletreated animals. Compounds of this invention should be efficacious inthis test procedure in the range of from about 0.1 mg/kg to about 100mg/kg.

DEPRESSION ASSAY

The antidepressant activity of the compounds of this invention can bedemonstrated in a tail suspension test using mice. A clinically usefulantidepressant which serves as a positive control in this assay isdesipramine. The method is based on the observations that a mousesuspended by the tail shows alternate periods of agitation andimmobility and that antidepressants modify the balance between these twoforms of behavior in favor of agitation. Periods of immobility in a 5minute test period are recorded using a keypad linked to a microcomputerwhich allows the experimenter to assign to each animal an identity codeand to measure latency, duration and frequency of immobile periods.Compounds of this invention should be efficacious in this test procedurein the range of from about 0.1 mg/kg to about 100 mg/kg.

SCHIZOPHRENIA ASSAY

The antidopaminergic activity of the compounds of this invention can bedemonstrated in an apomorphine-induced stereotypy model. A clinicallyuseful antipsychotic drug that is used as a positive control in thisassay is haloperidol. The assay method is based upon the observationthat stimulation of the dopaminergic system in rats produces stereotypedmotor behavior. There is a strong correlation between the effectivenessof classical neuroleptic drugs to block apomorphine-induced stereotypeand to prevent schizophrenic symptoms. Stereotyped behavior induced byapomorphine, with and without pretreatment with test compounds, isrecorded using a keypad linked to a microcomputer. Compounds of theinvention should be efficacious in this assay in the range of from about0.1 mg/kg to about 100 mg/kg.

In the treatment of the clinical conditions noted above, the compoundsof this invention may be utilized in compositions such as tablets,capsules or elixirs for oral administration, suppositories for rectaladministration, sterile solutions or suspensions for parenteral orintramuscular administration, and the like. The compounds of thisinvention can be administered to patients (animals and human) in need ofsuch treatment in dosages that will provide optimal pharmaceuticalefficacy. Although the dose will vary from patient to patient dependingupon the nature and severity of disease, the patient's weight, specialdiets then being followed by a patient, concurrent medication, and otherfactors which those skilled in the art will recognize, the dosage rangewill generally be about 5 to 6000 mg. per patient per day which can beadministered in single or multiple doses. Preferably, the dosage rangewill be about 10 to 4000 mg. per patient per day; more preferably about20 to 2000 mg. per patient per day.

In order to obtain maximal enhancement of cognitive function, thecompounds of this invention may be combined with othercognition-enhancing agents. These include acetylcholinesteraseinhibitors such as heptylphysostigmine and tetrahydroacridine (THA;tacrine), muscarinic agonists such as oxotremorine, inhibitors ofangiotensin-converting enzyme such as octylramipril, captopril,ceranapril, enalapril, lisinopril, fosinopril and zofenopril,centrally-acting calcium channel blockers and as nimodipine, andnootropic agents such as piracetam.

In order to achieve optimal anxiolytic activity, the compounds of thisinvention may be combined with other anxiolytic agents such asalprazolam, lorazepam, diazepam, and buspirone.

In order to achieve optimal antidepressant activity, combinations of thecompounds of this invention with other antidepressants are of use. Theseinclude tricyclic antidepressants such as nortriptyline, amitryptylineand trazodone, and monoamine oxidase inhibitors such as tranylcypromine.

In order to obtain maximal antipsychotic activity, the compounds of thisinvention may be combined with other antipsychotic agents such aspromethazine, fluphenazine and haloperidol.

The following examples illustrate the preparation of the compounds offormula (I) and their incorporation into pharmaceutical compositions andas such are not to be considered as limiting the invention set forth inthe claims appended hereto. All reactions as appropriate were carriedout under an atmosphere of dry nitrogen under standard conditions forthose skilled in the art.

EXAMPLE 12-n-Butyl-6-(morpholin-4-yl)-3-[(2'-(N-cyclopropanecarbonylsulfonamido)biphenyl-4-yl)methyl]quinazolin-4(3H)-oneStep A Preparation of methyl 5-chloro-2-nitrobenzoate

To a solution of 10 g (49.6 mmol) of 5-chloro-2-nitrobenzoic acid and 9mL (64.5 mmol) Et₃ N in 300 ml CH₂ Cl₂ at 0° C. was added 4.6 mL (59.5mmol) methyl chloroformate. The cold bath was removed and after 10minutes, 0.200 mL methanol was added. Bubbles of CO₂ could be seenrising from the solution. After 2 hours, the mixture was diluted withEt₂ O, was washed with 5% HCl, was washed with saturated NaHCO₃solution, was washed with brine, was dried over MgSO₄ and decolorizedwith charcoal, then was stripped of solvent in vacuo to give theproduct. R_(f) 0.35 in 15% EtOAc/hexane, visualized by UV; ¹ H-NMR (400MHz, CDCl₃): δ 7.92 (d, J=8.6 Hz, 1H), 7.69 (d, J=2.3 Hz, 1H), 7.59 (dd,J₁ =2.2 Hz, J₂ =8.8 Hz, 1H), 3.94 (s, 3H).

Step B Preparation of methyl 5-(morpholin-4-yl)-2-nitrobenzoate

A solution of 2.0 g (9.28 mmol) product from Step A and 1.6 mL (18.6mmol) morpholine in 20 mL DMF was heated to 90° C. for 6 hours. Afterthe mixture had cooled to room temperature, the DMF was stripped off invacuo. The crude material was then redissolved in methanol and stirredwith 20 g Amberlyst-A26® for about 20 minutes. The mixture was thenstripped of solvent and used without further purification in the nextstep. R_(f) 0.20 in 40% EtOAc/hexane, visualized by UV and visiblelight.

Step C Preparation of methyl 2-amino-5-(morpholin-4-yl) benzoate

The nitro compound from Step B above was dissolved in 75 mL THF and 25mL MeOH. This solution was added to about 2 g methanol-washed Raney®nickel (Aldrich, equivalent to W-2). The atmosphere above the solutionwas replaced with hydrogen and allowed to stir overnight. Afterreplacing the hydrogen atmosphere with nitrogen, the mixture was dilutedwith CH₂ Cl₂, and was filtered (CAUTION: Raney® nickel is pyrophoric andmust be kept wet, preferably with CH₂ Cl₂, to prevent ignition. Ablanket of nitrogen is also recommended. The catalyst was destroyed byadding water and concentrated HCl). The filtrate was stripped of solventin vacuo, and was chromatographed on silica gel under medium pressureusing 35% EtOAc/hexane to give 1.36 g of the product in, 62% yield over2 steps. R_(f) 0.21 in 40% EtOAc/hexane, visualized by UV and ninhydrinstain (black).

Step D Preparation of methyl5-(morpholin-4-yl)-2-pentanoylamino-benzoate

To a solution of 1.36 g (5.74 mmol) of product from Step C, 1.6 mL Et₃N, and about 15 mg DMAP in 20 mL DMF was added 0.886 mL (7.47 mmol)valeryl chloride. After 20 minutes the mixture was poured into NaHCO₃solution and extracted 3 times with ether. The combined organic materialwas dried over Na₂ SO₄, stripped of solvent in vacuo, and waschromatographed on silica gel under medium pressure using 30%EtOAc/hexane to give the product. R_(f) 0.29 in 40% EtOAc/hexane,visualized by UV and ammonium molybdate/ceric sulfate stain; ¹ H-NMR(400 MHz, CDCl₃): δ 10.75 (br s, 1H), 8.62 (d, J=9.2 Hz, 1H), 7.50 (d,J=2.9 Hz, 1H), 3.94 (dd, J1=3.0 Hz, J2=9.2 Hz, 1H), 3.90 (s, 3H), 3.85(3 line m, 4H), 3.10 (3 line m, 4H), 2.39 (3 line m, 2H), 1.71 (5 linem, 2H), 1.39 (6 line m, 2H), 0.93 (3 line m, 3H).

Step E Preparation of 2-n-butyl-6-(morpholin-4-yl) quinazolin-4(3H)-one

The ester obtained from Step D was heated to 65° C. for 10 minutes with2 mL 50% NaOH in 50 mL methanol. The mixture was cooled to roomtemperature then about 1 mg phenolphthalein was added. The mixture wasacidified with concentrated HCl until colorless. The mixture was dilutedwith brine and extracted 3 times with CH₂ Cl₂. The combined organicmaterial was washed with brine, dried over Na₂ SO₄, stripped of solventin vacuo to give 1.57 g of the free acid corresponding to the esterproduct of Step D, 89% yield over 2 steps. R_(f) 0.18 in 1/60/39HOAc/EtOAc/hexane, visualized by UV and ammonium molybdate/ceric sulfatestain (blue).

The acid (1.57 g, 5.11 mmol) was dissolved in 80 mL DMF to which wasadded 2.1 mL (15.3 mmol) Et₃ N, about 50 mg DMAP, and 0.728 mL (6.13mmol) valeryl chloride. After 10 minutes the mixture was heated to 110°C. After 1 hour, 3.8 g (30.7 mmol) ammonium carbonate was added overabout 8 minutes (CAUTION: Frothing occurs and could cause boilover).After 30 minutes the mixture was cooled to room temperature and pouredinto water. The precipitate was collected on filtration through a mediumfritted funnel. The solid was redissolved in methanol to which was added2 mL 50% NaOH. The mixture was heated to reflux for 30 minutes tocomplete the conversion of the bis-amide to quinazolinone. The mixturewas cooled to room temperature, phenolphthalein was added and themixture was acidified with concentrated HCl until colorless. Water wasadded and the precipitated solid was collected. The mother liquor washeated again and a second crop of crystals was taken to give a combinedtotal of 958 mg of product in 65% yield. R_(f) 0.25 in 40% EtOAc/hexane,visualized by UV and ammonium molybdate/ceric sulfate stain; ¹ H-NMR(400 MHz, DMSO-d₆): δ 11.99 (br s, 1H), 7.50 (m, 2H), 7.38 (m, 1H), 3.76(3 line m, 4H), 3.18 (3 line m, 4H), 2.55 (3 line m, 2H), 1.68 (5 linem, 2H), 1.33 (6 line m, 2H), 0.90 (3 line m, 3H).

Step F Preparation of2-n-butyl-6-(morpholin-4-yl)-3-[(2'-(N-t-butylsulfonamido)biphenyl-4-yl)methyl]quinazolin-4(3H)-one

To a solution of 200 mg (0.696 mmol) of product from Step E in 10 mL DMFwas added 31 mg (0.766 mmol) 60% NaH in oil followed by 319 mg (0.835mmol) [(2'-N-t-butylsulfonamido)biphenyl-4-yl]methyl bromide. Themixture was allowed to stir overnight. The mixture was diluted withbrine and extracted three times with Et₂ O. The combined organicmaterial was washed with brine, dried over Na₂ SO₄, stripped of solventin vacuo, was chromatographed on silica gel under medium pressure using1/40/59 AcOH/EtOAc/hexane, and was stripped in vacuo from toluene togive 262 mg of product in, 64% yield. R_(f) 0.11 in 1/40/59AcOH/EtOAc/hexane, visualized by UV (fluorescent blue under long-waveUV; O-alkylated material fluoresces yellow under long-wave UV and runsslightly higher on TLC); ¹ H-NMR (400 MHz, CDCl₃): δ 8.16 (4 line m,1H), 7.67-7.40 (mm, 8H), 7.27 (m, 2H), 5.46 (br, s, 2H), 3.90 (3 line m,4H), 3.49 (s, 1H), 3.28 (3 line m, 4H), 2.74 (3 line m, 2H), 1.79 (5line m, 2H), 1.43 (6 line m, 2H), 0.97 (s, 9H), 0.95 (3 line m, 3H).

Step G Preparation of2-n-butyl-6-(morpholin-4-yl)-3-[(2'-sulfonamidobiphenyl-4-yl)methyl]quinazolin-4(3H)-one

A solution of 262 mg (0.444 mmol) of product from Step F and 0.048 mL(0.444 mmol) anisole in TFA was stirred overnight. The TFA was removedin vacuo and the crude material was redissolved in CH₂ Cl₂ and washedwith saturated NaHCO₃ solution. Solvent was again removed in vacuo andthe material was recrystallized from hexane/CHCl₃ to give 169 mg of thetitle compound 109, 71% yield. R_(f) 0.21 in 60% EtOAc/hexane,visualized by UV (fluorescent blue under long-wave UV; ¹ H-NMR (400 MHz,CDCl₃): δ 8.16 (4 line m, 1H), 7.66-7.56 (mm, 3H), 7.54-7.40 (mm, 4H),7.29 (m, 3H), 5.47 (br s, 2H), 4.14 (s, 2H), 3.90 (3 line m, 4H), 3.28(3 line m, 4H), 2.77 (3 line m, 2H), 1.78 (5 line m, 2H), 1.43 (6 linem, 2H), 0.94 (3 line m, 3H).

Step H Preparation of2-n-butyl-6-(morpholin-4-yl)-3-[(2'-(N-cyclopropanecarbonylsulfonamido)biphenyl-4-yl)methyl]quinazolin-4(3H)-one

To a solution of 60 mg (0.113 mmol) of product from Step G and about 5mg DMAP in 6 mL pyridine was added 0.082 mL (0.901 mmol)cyclopropanecarbonyl chloride. After 2 hours 0.100 mL methanol was addedand the solution was stripped of pyridine in vacuo. The crude materialwas redissolved in CH₂ Cl₂ and washed with water. The organic layer wasextracted 3 times with 2% aqueous KOH. The combined aqueous material wasreacidified with AcOH and extracted three times with CH₂ Cl₂. Thecombined organic material was dried over Na₂ SO₄, stripped of solvent invacuo, was chromatographed on silica gel under medium pressure using1/10/89 NH₄ OH/MeOH/CH₂ Cl₂ then again in 1/60/39 AcOH/EtOAc/hexane, andwas stripped in vacuo from toluene to give 39 mg of the title compound,57% yield. R_(f) 0.15 in 1/10/89 NH₄ OH/MeOH/CH₂ Cl₂, visualized by UV;¹ H-NMR (300 MHz, CDCl₃): δ 8.25 (4 line m, 1H), 7.66-7.50 (mm, 4H),7.46-7.14 (mm, 6H), 5.46 (s, 2H), 3.89 (3 line m, 4H), 3.26 (3 line m,4H), 2.81 (3 line m, 2H), 1.81 (5 line m, 2H), 1.45 (6 line m, 2H), 1.06(m, 1H), 0.95 (3 line m, 3H), 0.86 (m, 2H), 0.66 (m, 2H); MS (FAB) m/e601 (M+1).

EXAMPLE 2 2-n-Butyl-6-(4-cyclopropanecarbonylpiperazin-1-yl)-3-[(2'-(N-cyclopropanecarbonylsulfonamido)biphenyl-4-yl)methyl]quinazolin-4(3H)-one.Step A Preparation of 2-n-butyl-6-(4-t-butoxycarbonylpiperazin-1-yl)quinazolin-4(3H)-one

A solution of 4.0 g (21.9 mmol) 5-chloro-2-nitrobenzonitrile, 4.90 g(26.3 mmol) t-butoxycarbonylpeperazine, and 6.1 ml (43.8 mmol) Et₃ N in20 mL DMF was heated to 70° C. for 6 hours. Solvent was removed invacuo, the crude product was partitioned between saturated NaHCO₃solution, brine, and CH₂ Cl₂. The organic layer was removed and theaqueous layer was extracted twice more with CH₂ Cl₂. The combinedorganic material was dried over Na₂ SO₄, stripped of solvent in vacuo togive 2-cyano-4-(4-t-butoxycarbonylpiperazin-1-yl) nitrobenzene. Thematerial was sufficiently pure to use without further purification.R_(f) 0.26 in 40% EtOAc/hexane, bright yellow under normal white light.

The nitro compound from above was hydrogenated using the same procedureas in Example 1, Step C. The crude product2-cyano-4-(4-t-butoxycarbonylpiperazin-1-yl) aniline, was acylated usingthe same procedure as Example 1, Step D. The crude product waschromatographed on silica gel under medium pressure using 45%EtOAc/hexane to give the corresponding amide. R_(f) 0.19 in 40%EtOAc/hexane, visualized by UV and ammonium molybdate/ceric sulfatestain.

The amide was dissolved in 100 mL methanol. To the solution was added 26mL (65.7 mmol) 2.5N NaOH and 15 mL 30% H₂ O₂. The solution was heated to60° C. for about three hours. Upon cooling to room temperature, themixture was acidified with concentrated HCl to the colorless point ofphenolphthalein. Brine was added and the mixture was extracted 3 timeswith CH₂ Cl₂. The combined organic material was dried over Na₂ SO₄,stripped of solvent in vacuo, and was recrystallized from EtOAc to give1.87 g2-n-butyl-6-(4-t-butoxycarbonylpiperazin-1-yl)quinazolin-4(3H)-one, 22%yield over 4 steps. R_(f) 0.19 in 60% EtOAc/hexane, visualized by UV(fluorescent light blue under long-wave UV); ¹ H-NMR (400 MHz, CDCl₃):δ9.88 (br s, 1H), 7.61 (m, 2H), 7.42 (dd, J₁ =2.9 Hz, J₂ =9.1 Hz, 1H),3.61 (3 line m, 4H), 3.25 (3 line m, 4H), 2.71 (3 line m, 2H), 1.81 (5line m, 2H), 1.49 (s, 9H), 1.47 (6 line m, 2H), 0.98 (3 line m, 3H).

Step B Preparation of2-n-butyl-6-(4-t-butoxycarbonylpiperazin-1-yl)-3-[(2'-(N-t-butylsulfonamido)biphenyl-4-yl)methyl]quinazolin-4(3H)-one

This compound was obtained using a procedure similar to that of Example1, Step F. Using 303 mg (0.785 mmol)2-n-butyl-6-(4-t-butoxycarbonylpiperazine-1-yl) quinazolin-4(3H)-one,300 mg (0.785 mmol) [(2'-N-t-butylsulfonamido)biphenyl-4-yl]methylbromide, 31 mg (0.863 mmol) 60% NaH in oil, in 10 mL DMF, 281 mg ofproduct was isolated after chromatography on silica gel under mediumpressure using 40% EtOA/hexane, 52% yield. R_(f) 0.10 in 40%EtOAc/hexane, visualized by UV (fluorescent blue under long-wave UV;O-alkylated material is fluorescest yellow under long-wave UV and runsslightly higher on TLC); ¹ H-NMR (400 MHz, CDCl₃): δ 8.16 (d, J=8.0 Hz,1H), 7.67-7.41 (mm, 7H), 7.27 (m, 3H), 5.46 (br s, 2H), 3.61 (3 line m,4H), 3.49 (s, 1 H), 3.26 (3 line m, 4H), 2.74 (3 line m, 2H), 1.78 (5line m, 2H), 1.49 (s, 9H), 1.43 (6 line m, 2H), 0.97 (s, 9H), 0.94 (3line m, 3H).

Step C Preparation of2-n-butyl-6-piperazin-1-yl)-3-[(2'-sulfonamidobyphenyl-4-yl)methyl]quinazolin-4(3H)-one

This compound was obtained using a procedure similar to that used inExample 1 Step G. Using 276 mg (0.401 mmol) product from Step B and0.087 mL (0.802 mmol) anisole, in 10 mL TFA, 105 mg product was isolatedafter stripping off the TFA in vacuo, treating with saturated NaHCO₃ andextracting with CH₂ Cl₂, drying over Na₂ SO₄, and recrystallizing fromhexane/MeOH/CHCl₃, 49% yield. R_(f) 0.25 in 1/10/89 NH₄ OH/MeOH/CH₂ Cl₂,visualized by UV.

Step D Preparation of2-n-butyl-6-(4-cyclopropanecarbonylpiperazin-1-yl)-3-[(2'-N-cyclopropanecarbonylsulfonamidobiphenyl-4-yl)methyl]quinazolin-4(3H)-one

This compound was obtained using a procedure similar to that used inExample 1 Step H. Using 105 mg (0.197 mmol) product of Step C, about 5mg DMAP, 0.179 mL (1.97 mmol) cyclopropanecarbonyl chloride, in 10 mLpyridine, 127 mg of product was isolated after addition of 0.100 mLMeOH, stripping of solvents in vacuo, addition of water and extractionwith CH₂ Cl₂, drying over Na₂ SO₄, stripping from toluene in vacuo, andchromatography on silica gel under medium pressure using 1/75/24AcOH/EtOAc/hexane, and again stripping from toluene in vacuo, 96% yield.R_(f) 0.22 in 1/75/24 AcOH/EtOAc/hexane, visualized by UV (fluorescentblue under long-wave UV) and ammonium molybdate/ceric sulfate stain; ¹H-NMR (400 MHz, CDCl₃): δ 8.25 (4 line m, 1H), 7.62 (m, 2H), 7.59-7.51(m, 2H), 7.44 (4 line m, 1H), 7.36-7.20 (4 line m, 4H), 7.28 (4 line m,1H), 5.44 (br s, 2H), 3.86 (br m, 4H), 3.31 (br m, 4H), 2.81 (3 line m,2H), 1.81 (mm, 3H), 1.44 (6 line m, 2H), 1.10 (m, 1H), 1.03 (m, 2H),0.95 (3 line m, 3H), 0.86 (m, 2H), 0.82 (m, 2H), 0.66 (m, 2H); MS (FAB)m/e 668 (M+1).

Employing procedures substantially as described in Example 2 withappropriate starting materials the compounds described in Table III wereprepared.

                                      TABLE III                                   __________________________________________________________________________     ##STR98##                                                                                                         Mass Spec (FAB)                          Ex.  RE      G            Z          m/e                                      __________________________________________________________________________    3.   n-C.sub.3 H.sub.7                                                                      ##STR99##                                                                                  ##STR100##                                                                              663 (M + 1)                              4.   n-C.sub.3 H.sub.7                                                                      ##STR101##                                                                                 ##STR102##                                                                              654 (M + 1)                              5.   n-C.sub.3 H.sub.7                                                                      ##STR103##                                                                                 ##STR104##                                                                              587 (M + 1)                              6.   n-C.sub.4 H.sub.9                                                                      ##STR105##                                                                                 ##STR106##                                                                              563 (M + 1)                              __________________________________________________________________________

EXAMPLE 7 Typical Pharmaceutical Compositions Containing a Compound ofthe Invention as Active Ingredient A: Dry Filled Capsules Containing 50mg of Active Ingredient Per Capsule

    ______________________________________                                        Ingredient    Amount per capsule (mg)                                         ______________________________________                                        Active Ingredient                                                                            50                                                             Lactose       149                                                             Magnesium stearate                                                                           1                                                              Capsule (size No. 1)                                                                        200                                                             ______________________________________                                    

The active ingredient can be reduced to a No. 60 powder and the lactoseand magnesium stearate can then be passed through a No. 60 blottingcloth onto the powder. The combined ingredients can then be mixed forabout 10 minutes and filled into a No. 1 dry gelatin capsule.

B: Tablet

A typical tablet would contain the active ingredient (25 mg),pregelatinized starch USP (82 mg), microcrystalline cellulose (82 mg)and magnesium stearate (1 mg).

C: Combination Tablet

A typical combination tablet would contain, for example, a diuretic suchas hydrochlorothiazide and consist of the active ingredient (50 mg)pregelatinized starch USP (82 mg), microcrystalline cellulose (82 mg)and magnesium stearate (1 mg).

D: Suppository

Typical suppository formulations for rectal administration can containthe active ingredient (1-25 mg), butylated hydroxyanisole (0.08-1.0 mg),disodium calcium edetate (0.25-0.5 mg), and polyethylene glycol(775-1600 mg). Other suppository formulations can be made bysubstituting, for example, butylated hydroxytoluene (0.04-0.08 mg) forthe disodium calcium edetate and a hydrogenated vegetable oil (675-1400mg) such as Suppocire L, Wecobee FS, Wecobee M, Witepsols, and the like,for the polyethylene glycol. Further, these suppository formulations canalso include another active ingredient such as another antihypersiveand/or a diuretic and/or an angiotension converting enzyme and/or acalcium channel blocker in pharmaceutically effective amounts asdescribed, for example, in C above.

E: Injection

A typical injectible formulation would contain the active ingredient(5.42 mg), sodium phosphate dibasic anhydrous (11.4 mg) benzyl alcohol(0.01 ml) and water for injection (1.0 ml). Such an injectibleformulation can also include a pharmaceutically effective amount ofanother active ingredient such as another antihypertensive and/or adiuretic and/or an angiotension converting enzyme inhibitor and/or acalcium channel blocker.

What is claimed is:
 1. A compound of structural formula: ##STR107## or a pharmaceutically acceptable salt thereof, wherein: G is(1) R¹ or ##STR108## E is (1) a single bond, (2) --CH(OH)--, (3) --O--, (4) --CO--, (5) --S(O)_(x) (CH₂)_(s) --wherein x is 0, 1, or 2, and s is 0-5, or (6) --NR³ (CH₂)_(s) -- wherein R³ is(a) --H, (b) C₂₋₄ alkanoyl, (c) C₁₋₆ alkyl, (d) C₂₋₆ alkenyl, (e) C₃₋₇ cycloalkyl, (f) phenyl, or (g) benzyl; R is(1) aryl, (2) heteroaryl, (3) C₃₋₇ cycloalkyl, (4) polyfluoro-C₁₋₄ alkyl, (5) --H, (6) C₂₋₆ alkenyl, (7) C₂₋₆ alkynyl, (8) C₁₋₆ alkyl, either unsubstituted or substituted with:(a) aryl, (b) C₃₋₇ cycloalkyl, (c) halo, (d) --NH₂, (e) --NH(C₁₋₄ alkyl), (f) --N(C₁₋₄ alkyl)₂, (g) --OR⁴, wherein R⁴ is(i) --H, (ii) aryl, (iii) heteroaryl, (iv) C₁₋₆ alkyl, or (v) aryl-C₁₋₆ alkyl; (h) --COOR⁴, (i) --NHSO₂ R⁴, or (j) --SO₂ NHR⁵, wherein R⁵ is(i) --H (ii) C₁₋₅ alkyl, (iii) aryl or (iv) --CH₂ --aryl; R¹ is(1) --CO₂ R⁴ (2) --SO₃ R⁶, wherein R⁶ is(a)--H (b)--CH(R⁴)--O--CO--R^(4a) wherein R^(4a) is(i) C₁₋₆ alkyl, (ii) aryl or (iii) --CH₂ --aryl; (3) --P(O)(OR⁶)₂, (4) --CONHNHSO₂ CF₃, (5) --SO₂ NHCN, (6) --P(O)(OR⁶)(OR⁴), (7) --SO₂ NHR⁷, wherein R⁷ is(a) --H (b) aryl, (c) heteroaryl, (d) C₃₋₇ cycloalkyl, (e) polyfluoro-C₁₋₄ alkyl, or (f) C₁₋₁₀ alkyl, either unsubstituted or substituted with:(i) aryl, (ii) heteroaryl, (iii) --OH, (iv) --SH, (v) C₁₋₄ alkoxy, (vi) C₁₋₄ alkylthio (vii) halo (viii) --NO₂ (ix) --CO₂ R¹¹, wherein R¹¹ is --H or C₁₋₄ alkyl, (x) --NH₂, (xi) --NH(C₁₋₄ alkyl) (xii) --N(C₁₋₄ alkyl)₂ (xiii) --PO₃ H₂, (xiv) --P(O)(OH)(OC₁₋₄ alkyl), or (xv) --P(O)(OR⁴)(R⁸) wherein R⁸ is(a) --H (b) --C₁₋₅ alkyl, (c) -aryl or (d) --CH₂ --aryl, (8) --NHSO₂ R⁷, (9) --SO₂ NHCOR⁷, (10) --CH₂ SO₂ NHCOR⁷, (11) --CONHSO₂ R⁷, (12) --CH₂ CONHSO₂ R⁷, (13) --NHSO₂ NHCOR⁷, (14) --NHCONHSO₂ R⁷, (15) --SO₂ NHCONR⁴ R⁷, (16) --CH₂ SO₂ NHR⁷, (17) --C(OH)(R⁸)--P(O)(OR⁶)₂, (18) --P(O)(R⁸)(OR⁶), (19) tetrazol-5-yl, substituted with R⁹ wherein R⁹ is(a) --H, (b) C₁₋₆ alkyl, (c) C₂₋₄ alkenyl, (d) C₁₋₄ alkoxy-C₁₋₄ alkyl (e) benzyl, either unsubstituted or substituted with(i) --NO₂, (ii) --NH₂, (iii) --OH, or (iv) --OCH₃, (20) --CH₂ -tetrazol-5-yl substituted with R⁹, (21) --CONH-tetrazol-5-yl substituted with R⁹, (22) --1,3,4-triazol-2-yl substituted with R¹⁰ wherein R¹⁰ is(a) --CN, (b) --NO₂, (c) --CF₃ or (d) --CO₂ R⁴ ; (23) 1,2,3-triazol-4-yl substituted with R¹⁰, (24) --SO₂ NHSO₂ R⁷, (25) --OH or ##STR109## R² is: (1) --H, (2) --CO-aryl, (3) C₃₋₇ cycloalkyl, (4) halo, (5) --OH, (6) --OR⁷ (7) polyfluoro-C₁₋₄ alkyl, (8) --S(O)_(x) R⁷, (9) --COOR⁴, (10) --SO₂ H, (11) --NR⁴ R⁷, (12) --NHCOR⁷, (13) --NHCO₂ R⁷ (14) --SO₂ NR⁸ R¹¹, wherein R¹¹ is(a) --H or (b) C₁₋₄ alkyl, (15) --NO₂ (16) --NHSO₂ R⁷ (17) --NHCONR⁴ R⁷, (18) --OCONR⁷ R⁸, (19) aryl, (20) heteroaryl, (21) --NHSO₂ polyfluorophenyl, (22) --SO₂ NH--heteroaryl, (23) --SO₂ NHCOR⁷, (24) --CONHSO₂ R⁷, (25) --PO(OR⁴)₂, (26) --PO(OR⁴)R⁸, (27) tetrazol-5-yl, (28) --CONH(tetrazol-5-yl), (29) --COR⁴ (30) --SO₂ NHCN, (31) --CO--heteroaryl, (32) --NHSO₂ NR⁷ R⁸, or (33) C₁₋₆ alkyl, either unsubstituted or substituted with(a) --OH, (b) --guanidino, (c) --C₁₋₄ alkoxy, (d) --N(R⁴)₂, (e) --CO₂ R⁴, (f) --CON(R⁴)₂, (g) --O--COR⁴ (h) -aryl, (i) -heteroaryl, (j) --S(O)_(x) R⁷ (k) -tetrazol-5-yl, (l) --CONHSO₂ R⁷, (m) --SO₂ NH--heteroaryl, (n) --SO₂ NHCOR⁷, (o) --PO(OR⁴)₂, (p) --PO(OR4)R⁹, (q) --SO₂,NHCN, (r) --NR¹¹ COOR⁷, (s) -morpholino, (t) --N(C₁₋₆ alkyl)piperazine or (u) --COR⁴, with the proviso that the R² groups can be the same or different; or two R² groups joined to the same carbon taken together represent(a) =O (b) =S or (c) --[(CH₂)₂₋₆ ]--; R^(2a), R^(2b), R^(3a) and R^(3b) independently represent(1) C₁₋₅ alkyl, (2) polyfluoro-C₁₋₅ alkyl, (3) halo; (4) hydroxy or (5) C₁₋₅ alkoxy; U, V and W are --CH═ or Z is:(1) --O--, (2) --S(O)_(x) -- (3) --N(R¹²)-- wherein R¹² is(a) --H or (b) --R¹³ wherein R¹³ is(i) C₁₋₄ alkyl, (ii) C₃₋₇ cycloalkyl (iii) aryl, (iv) heteroaryl, (v) polyfluoro-C₁₋₄ alkyl, (vi) polyfluoro-C₃₋₇ cycloalkyl, or (vii) polyfluorophenyl; (4) --N(COR¹³)--, (5) --N(CONHR¹³)--, (6) --N(CON(R¹³)₂)--, (7) --N(CO₂ R¹³)--, (8) --N(SO₂ NHR¹³)--, (9) --N(SO₂ N(R¹³)₂)--, (10) --N(SO₂ R¹³)--, or (11) --C(R²)₂ --, X is(1) a single bond (2) --SO₂ -- (3) --O-- (4) --C(R²)₂ -- (5) --N(R¹²)-- (6) --N(COR¹³)-- (7) --N(CONHR¹³)-- (8) --N(CON(R¹³)₂)-- (9) --N(CO₂ R¹³)-- (10) --N(SO₂ NHR¹³)-- (11) --N(SO₂ N(R¹³)²)-- (12) --N(SO₂ R¹³)-- Y is(1) --O-- (2) --S(O)_(x) -- where x is 0, 1, or 2, (3) --C(R²)₂ -- (4) --N(R¹²)-- (5) --N(COR¹³)-- (6) --N(CONHR¹³)-- (7) --N(CON(R¹³)₂)-- (8) --N(CO₂ R¹³)-- (9) --N(SO₂ NHR¹³)-- (10) --N(SO₂ N(R¹³)₂)-- (11) --N(SO₂ R¹³)--.
 2. The compound of claim 1 wherein G is ##STR110##
 3. The compound of claim 2 wherein:E is(1) a single bond, (2) --O-- or (3) --S--; R is(1) C₁₋₆ alkyl, either unsubstituted or substituted with:(a) C₃₋₅ cycloalkyl, (b) --Cl, (c) --CF₃, (d) --OCH₃, (e) --OC₂ H₅, (f) --SCH₃, (g) --SC₂ H₅ (h) --F, or (i) phenyl; (2) C₂₋₅ alkenyl, (3) C₂₋₅ alkynyl, or (4) C₃₋₅ cycloalkyl; R¹ is(1) --CO₂ H, (2) tetrazol-5-yl, (3) --NHSO₂ R⁷, (4) --SO₂ NH--heteroaryl, (5) --CH₂ SO₂ NH-heteroaryl, (6) --SO₂ NHCOR⁷, (7) --CH₂ SO₂ NHCOR⁷, (8) --CONHSO₂ R⁷, (9) --CH₂ CONHSO₂ R⁷ (10) --₂ NHSO₂ NHCOR⁷ or (11) --NHCONHSO₂ R⁷ (12) --SO₂ NHCON(R⁴)R⁷ (13) --SO₂ NHCON Z R² is:(1) H, (2) C₁₋₄ alkyl, either unsubstituted or substituted with:(a) --CO₂ R⁴, (b) --OCOR^(4a), (c) --OH, or (d) --aryl; (3) C₂₋₄ alkenyl, (4) --OH, (5) -NO₂, (6) -NHCOR⁷, (7) --C₁₋₄ alkoxy, (8) --NHCO₂ R⁷, (9) --NR⁴ R⁷ or (10) --Cl, --F, or --Br; or two R² groups on the same carbon taken together represent ═O or --(CH₂)₂₋₅ --; and X is(1) --C(R²)₂ -- or (2) a single bond; Y is(1) --C(R²)₂ -- or (2) --N(R¹²)₂ --; Z is(1) --N(R¹²)--, (2) --N(COR¹³)--, (3) --N(CONHR¹³)--, or (4) --N(CON(R¹³)₂)--, (5) --O-- (6) --S--.
 4. The compound of claim 3 of structural formula: ##STR111## or a pharmaceutically acceptable salt thereof selected from the group of compounds consisting of those in the following table:

    ______________________________________                                         RE       R.sup.1           Z                                                   ______________________________________                                         n-C.sub.4 H.sub.9                                                                        ##STR112##       O                                                   n-C.sub.4 H.sub.9                                                                        ##STR113##                                                                                       ##STR114##                                         n-C.sub.3 H.sub.7                                                                        ##STR115##                                                                                       ##STR116##                                         n-C.sub.3 H.sub.7                                                                        ##STR117##                                                                                       ##STR118##                                         n-C.sub.3 H.sub.7                                                                        ##STR119##                                                                                       ##STR120##                                         n-C.sub.4 H.sub.9                                                                        ##STR121##                                                                                       ##STR122##                                         ______________________________________                                    


5. The compound of claim 1 wherein G is R¹.
 6. The compound of claim 5 wherein:E is(1) a single bond, (2) --O-- or (3) --S--; R is(1) C₁₋₆ alkyl, either unsubstituted or substituted with:(a) C₃₋₅ cycloalkyl, (b) --Cl, (c) --CF₃, (d) --OCH₃, (e) --OC₂ H₅, (f) --SCH₃, (g) --SC₂ H₅ (h) --F, or (i) phenyl; (2) C₂₋₅ alkenyl, (3) C₂₋₅ alkynyl, or (4) C₃₋₅ cycloalkyl; R¹ is(1) --CO₂ H, (2) tetrazol-5-yl, (3) --NHSO₂ R⁷, (4) --SO₂ NH-heteroaryl, (5) --CH₂ SO₂ NH-heteroaryl, (6) --SO₂ NHCOR⁷, (7) --CH₂ SO₂ NHCOR⁷, (8) --CONHSO₂ R⁷, (9) --CH₂ CONHSO₂ R⁷ (10) --₂ NHSO₂ NHCOR⁷ or (11) --NHCONHSO₂ R⁷ (12) --SO₂ NHCON(R⁴)R⁷ (13) --SO₂ NHCON Z R² is:(1) H, (2) C₁₋₄ alkyl, either unsubstituted or substituted with:(a) --CO₂ R⁴, (b) --OCOR^(4a), (c) --OH, or (d) -aryl; (3) C₂₋₄ alkenyl, (4) --OH, (5) --NO₂, (6) --NHCOR⁷, (7) --C₁₋₄ alkoxy, (8) --NHCO₂ R⁷, (9) --NR⁴ R⁷ or (10) --Cl, --F, or --Br; or two R² groups on the same carbon taken together represent ═O; and X is(1) --C(R²)₂ -- or (2) a single bond; Y is(1) --C(R²)₂ -- or (2) --N(R¹²)₂ --; Z is(1) --N(R¹²)--, (2) --N(COR¹³)--, (3) --N(CONHR¹³)--, or (4) --N(CON(R¹³)₂)--, (5) --O-- (6) --S--.
 7. The compound of claim 6 wherein E-R is ##STR123##
 8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim
 1. 9. The composition of claim 8 which includes another antihypertensive selected from a diuretic selected from hydrochlorothiazide, chlorothiazide, chlorthalidone, methyclothiazide, furosemide, ethacrynic acid, triamterene, amiloride, atriopeptin and spironolactone; a calcium channel blocker, selected from diltiazem, felodipine, nifedipine, amlodipine, rumodipine, isradapine, nitrendipine and verapamil; a β-adrenergic antagonist selected from timolol, atenolol, metoprolol, propanolol, nadolol and pindolol; an angiotensin converting enzyme inhibitor selected from enalapril, lisinopril, captopril, ramipril, quinapril and zofenopril; a renin inhibitor selected from A-69729, FK-906 and FK-744; an α-adrenergic antagonist selected from prazosin, doxazosin, and terazosin; a sympatholytic agent selected from methyldopa, clonidine and guanabenz; the atriopeptadase inhibitor UK-79300 (alone or with ANP); the serotonin antagonist, ketanserin; the A₂ -adenosine receptor agonist CGS 22492C; a potassium channel agonist selected from pinacidil and cromakalim; another antihypertensive drug selected from reserpine, minoxidil, guanethidine, hydralazine, hydrochloride and sodium nitroprusside; a cardiac stimulant selected from dobutamine and xamoterol; a phosphodiesterase inhibitor selected from amrinone and milrinone or combinations of the above-named drugs.
 10. A method of treating hypertension which comprises administering to a patient in need of such treatment a pharmaceutically effective amount of a compound of claim
 1. 11. An ophthalmological formulation for the treatment of ocular hypertension comprising an ophthalmologically acceptable carrier and an effective ocular antihypertensive amount of a compound of claim
 1. 12. A method of treating ocular hypertension comprising administering to a patient in need of such treatment an effective ocular antihypertensive amount of a compound of claim
 1. 